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Abstract:

The invention relates to improved drug-delivery endoprosthetic device for
insertion at a vascular site via catheter placement at the site,
comprising: (a) a structural member into the upper and/or lower surface
of which one or more micro-deepenings are engraved and/or on which a
polymer member is carried, for co-expansion with the polymer member from
a contracted state to an expanded state when the device is exposed to
said stimulus, (b) optionally a polymer member capable of expanding from
a contracted to a stable, expanded state when the polymer member is
exposed to a selected stimulus,wherein the device can be delivered from a
catheter, with the structural and the optional polymer members in their
contracted states, and is adapted to be held in a vessel at the vascular
target site by radial pressure against the wall of the vessel, with the
structural and the optional polymer members in their expanded states;
andwherein the micro-deepenings of said structural member and/or said
polymer member comprise a pharmaceutical composition containing one or
more active ingredients selected from the group consisting of agents to
inhibit or at least reduce excessive proliferation of vessel wall cells,
agents to enhance the downstream perfusion of tissue, agents to promote
and/or to enhance the neo-formation of capillaries, agents designed to
modulate the amount or activity of coagulation factors, agents to reduce
the amount of Thrombin- and/or Fibrin-formation, embedded therein for
release from the member, with such in its expanded state.

Claims:

1. In an endoprosthetic device for insertion at a vascular site via
catheter placement at the site which device comprises a structural member
into the upper or lower surface of which one or more micro-deepenings are
engraved or on which a polymer member is carried for co-expansion with
the polymer member from a contracted state to an expanded state when the
device is exposed to said stimulus, or having a polymer member capable of
expanding from a contracted to a stable, expanded state when the polymer
member is exposed to a selected stimulus, where the device is delivered
from a catheter with the structural and the optional polymer members in
their contracted states, and is adapted to be held in a vessel at the
vascular target site by radial pressure against the wall of the vessel,
with the structural and the optional polymer members in their expanded
states and wherein the micro-deepenings of said structural member or said
polymer member comprise a pharmaceutical composition containing one or
more active ingredients selected from the group consisting of agents to
inhibit or at least reduce excessive proliferation of vessel wall cells,
agents to enhance the downstream perfusion of tissue, agents to promote
or to enhance the neo-formation of capillaries, agents designed to
modulate the amount or activity of coagulation factors, agents to reduce
the amount of Thrombin- or Fibrin-formation, embedded therein for release
from the member, with such in its expanded state, the improvement which
comprises that said pharmaceutical composition comprises at least one
pyrimido-pyrimidine compound selected from dipyridamole, mopidamol and
the pharmaceutically acceptable salts thereof, optionally in combination
with one or more other antithrombotic agents, agents to enhance lysis of
fibrin, agents to locally arrest cell proliferation in a reversible or in
an irreversible manner, a gene transfer protein, an inhibitor of
metallo-protease, a statin, an antifungal antibiotic such as rapamycin,
an ACE inhibitor, an Angiotensin II antagonist, an ADP receptor
inhibitor, a Ca-antagonist and/or a lipid-lowering agent.

2. The device of claim 1 wherein the different active ingredients can be
eluted simultaneously.

3. The device of claim 1 wherein the different active ingredients can be
eluted in a specified sequence and with different eluation
characteristics.

4. The device of claim 1 wherein the pyrimidopyrimidine is dipyridamole.

5. The device of claim 1 wherein the pyrimido-pyrimidine is in sufficient
amount so that a plasma level of about 0.2 to 5 μmol/L thereof is
maintained.

6. The device of claim 1 wherein the pyrimido-pyrimidine is administered
in a dosage of 0.5 to 5 mg/kg body weight during 24 hours.

7. The device of claim 1 wherein the pharmaceutical composition comprises
the pyrimido-pyrimidine in combination with an organic acid or a
derivative thereof.

9. The device of claim 1, wherein said polymer member is composed of a
shape-memory polymer responsive to a thermal stimulus at a temperature
from about 25.degree. to 100.degree. C.

10. The device according to claim 1, wherein said polymer member is
coextensive with said structural member.

11. The device according to claim 10, wherein said polymer member encases
said structural member and, in its contracted state, is effective to
restrain said structural member in its contracted state.

12. The device according to claim 1, wherein said thermally-responsive
polymer member is formed of a memory polymer having a thermally-activated
polymer-state transition selected from the group consisting of:(a) a
melting point of the polymer;(b) a glass-transition of the polymer;(c) a
liquid crystal transition; and(d) a local mode molecular transition.

13. The device of claim 12, wherein said polymer member is an
acrylate-containing or a methacrylate-containing polymer.

14. The device according to claim 1, wherein said structural member is
responsive to a stimulus selected from the group consisting of heat and
radial force.

15. The device according to claim 1, wherein said structural member is a
metal or alloy selected from the group consisting of Nitinol, stainless
steel, titanium, tantalum, cobalt, platinum, and iridium.

16. The device according to claim 1, wherein said structural member is
composed of a shape-memory alloy for radial expansion at a critical
temperature by activating a heat-recoverable memory diameter and said
device is heated to said critical temperature.

17. The device according to claim 1, wherein said structural member is
composed of a heat-activated, shape memory polymer.

18. The device according to claim 1, wherein said structural member is
composed of a metal and designed for self-expansion.

19. The device according to claim 1, wherein said pharmaceutical
composition comprises dipyridamole or a pharmaceutically acceptable salt
thereof, in combination with heparin and/or Clopidogrel.

20. The device according to claim 1, wherein said polymer member is
carried on said structural member by attaching said polymer member to
said structural member by an adhesive.

21. The device of claim 20, wherein said adhesive is a biopolymer selected
from the group consisting of proteins and peptides.

22. The device of claim 20, wherein said adhesive is prepared from a
synthetic polymer which swells or dissolves in water.

23. The device according to claim 1, wherein the micro-deepenings cover up
to 40% of the upper and/or lower surface and are engraved for up to 80%
of the height of the perimeter of the structural element.

24. A method for treating or preventing fibrin-dependent microcirculation
disorders or of disease states where such microcirculation disorders are
involved in a warm-blooded animal, said method comprising insertion of a
device according to claim 1 at a vascular site via catheter placement at
such site.

Description:

RELATED APPLICATIONS

[0001]This application is a continuation of U.S. application Ser. No.
11/949,142, filed Dec. 3, 2007, which is a continuation of U.S.
application Ser. No. 11/119,083, filed Apr. 29, 2005, which is a
continuation of U.S. application Ser. No. 10/283,518, filed Oct. 30,
2002, which claims as does the present application priority to U.S.
Provisional Application Ser. No. 60/332,246, filed Nov. 16, 2001, and
EP01125840, filed Oct. 30, 2001, the disclosure of all of which are
incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002]Endoprosthetic devices known as stents are placed or implanted
within a vessel for treating problems such as stenoses, strictures, or
aneurysms in the vessel. Typically, these devices are implanted in a
vessel to reinforce collapsing, partially occluded, weakened or dilated
vessels. Stents may also be implanted in the urethra, ureter, bile duct,
or any body vessel which has been narrowed or weakened.

[0003]Stents made of various materials including metals, alloys and
plastics and formed into variety of geometric shapes have been described
in the art. Two types of stents have been commonly employed. Spring-like
or self-expanding stents, formed typically of metals or alloys, are
inserted into the target vessel with a restraining element or sheath over
the stent, to prevent the stent from expanding until placement at the
target site. The other type of stent requires a stimulus to expand the
stent after placement at the target vessel. Most often, this stimulus is
radial force or pressure applied by inflation of a balloon on a catheter.
Stents which respond to other stimuli, such as heat, are also known, and
these stents are generally composed of a shape-memory material, either an
alloy or a polymer.

[0004]It is often desirable to administer a drug at the target site, where
the stent also serves as a framework for carrying the therapeutic
compound. Numerous approaches have been proposed and, for metal stents,
one proposed approach is to directly coat the stent wires with a polymer
containing the therapeutic agent. This approach suffers from several
problems including cracking of the polymer as the stent is expanded
during deployment. Because the stent wires have a limited surface area,
and because the overall polymer coating should be thin so that it will
not significantly increase the profile of the stent, the amount of
polymer that can be applied is limited. Hence, another disadvantage with
polymer-coated stents for drug delivery is a limited capacity of the
polymer for carrying a drug.

[0005]Another approach to providing delivery of a drug in combination with
a stent has been to include a sheath, which encompasses the stent and
contains the therapeutic agent. (U.S. Pat. No. 5,383,928; U.S. Pat. No.
5,453,090). Such sheaths are typically secured to the stent by means of a
hemostat or other clamping mechanism, which have the disadvantage of
increasing the profile of the catheter, reducing flexibility and
tractability.

[0006]A major problem with all stents is that the stents themselves induce
a vascular smooth muscle cell proliferation, which can lead to
significant restenosis within a few months.

BRIEF SUMMARY OF THE INVENTION

[0007]The present invention relates to an improved endoprosthetic device
for insertion in a vessel and simultaneous administration of a
therapeutic compound. Accordingly, it is an object of the invention to
provide a stent which overcomes the above-mentioned problems. It has now
been found, surprisingly, that the vascular smooth cell proliferation
caused by stents can be reduced if said stent comprises a
pyrimidino-pyrimidine compound.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008]FIG. 1 is a cross-sectional view of a strut of a stent according to
the present invention.

[0009]FIG. 2 shows a strut network for a stent according to the present
invention.

[0010]FIG. 3 shows a stent according to the present invention.

[0011]FIG. 4 is a cross-sectional view of a strut for use in a stent
according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0012]Dipyridamole
{2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine}, and
closely related substituted pyrimido-pyrimidines and their preparation
have been described in e.g. U.S. Pat. No. 3,031,450. Further related
substituted pyrimido-pyrimidines and their preparation have been
described in e.g. GB 1,051,218, inter alia, the compound mopidamol
{2,6-bis(diethanolamino)-4-piperidinopyrimido[5,4-d]pyrimidine}.

[0013]Dipyridamole was introduced as a coronary vasodilator in the early
1960s. It is also well known having platelet aggregation inhibitor
properties due to the inhibition of adenosine uptake. Subsequently,
dipyridamole was shown to reduce thrombus formation in a study of
arterial circulation of the brain in a rabbit model. These investigations
led to its use as an antithrombotic agent; it soon became the therapy of
choice for such applications as stroke prevention, maintaining the
patency of coronary bypass and valve-replacement, as well as for
treatment prior to coronary angioplasty.

[0014]European patent application EP 0 543 653 suggests the use of
dipyridamole for the preparation of a formulation adapted for local
delivery to proliferative cells. There is no mention, however, of stents
comprising dipyridamole.

[0015]Mopidamol is known to possess antithrombotic properties and is also
known to possess antimetastatic properties.

[0016]In one aspect, the invention includes an improved drug-delivery
endoprosthetic device for insertion at a vascular site via catheter
placement, which device comprises: [0017]a structural member into the
upper and/or lower surface of which one or more micro-deepenings are
engraved and/or on which a polymer member is carried, for co-expansion
with the polymer member from a contracted state to an expanded state when
the device is exposed to said stimulus. Optionally a polymer member
capable of expanding from a contracted to a stable, expanded state when
the polymer member is exposed to a selected stimulus is also employed.

[0018]The device can be delivered from a catheter, with the structural and
the optional polymer members in their contracted states, and is adapted
to be held in a vessel at the vascular target site by radial pressure
against the wall of the vessel, with the structural and the optional
polymer members in their expanded states; and

wherein the micro-deepenings of said structural member and/or said polymer
member comprise a pharmaceutical composition containing one or more
active ingredients selected from the group consisting of agents to
inhibit or at least reduce excessive proliferation of vessel wall cells,
agents to enhance the downstream perfusion of tissue, agents to promote
and/or to enhance the neo-formation of capillaries, agents designed to
modulate the amount or activity of coagulation factors, agents to reduce
the amount of Thrombin- and/or Fibrin-formation, embedded therein for
release from the member, with such in its expanded state,the improvement
wherein is that said pharmaceutical composition comprises at least one
pyrimido-pyrimidine compound selected from dipyridamole, mopidamol and
the pharmaceutically acceptable salts thereof, optionally in combination
with one or more other antithrombotic agents, agents to enhance lysis of
fibrin, agents to locally arrest cell proliferation in a reversible or in
an irreversible manner, a gene transfer protein, an inhibitor of
metallo-protease, a statin, an antifungal antibiotic such as rapamycin,
an ACE inhibitor, an Angiotensin TI antagonist, an ADP receptor
inhibitor, a Ca-antagonist and/or a lipid-lowering agent.

[0019]The device may include a shape-memory polymer member capable of
expanding from a contracted state to a stable, radially expanded state
when the polymer member is exposed to a selected stimulus.

[0020]In one embodiment, the polymer member is composed of a shape-memory
polymer responsive to a thermal stimulus at a temperature between about
25°-100° C.

[0021]The polymer member is coextensive with the structural member, or, in
other embodiments, the polymer member encases the structural member and,
in its contracted state, is effective to restrain the structural member
in its contracted state.

[0022]In one embodiment, the thermally-responsive polymer member is formed
of a memory polymer having a thermally-activated polymer-state transition
which is a melting point of the polymer; a glass-transition of the
polymer; a liquid crystal transition; or a local mode molecular
transition. Such a polymer can be an acrylate-containing or a
methacrylate-containing polymer.

[0023]In another embodiment, the structural member expands in response to
a heat stimulus or radial force. Preferably, such a structural member
composed of a metal or alloy such as Nitinol, stainless steel, titanium,
tantalum, cobalt, platinum, and iridium.

[0024]Another aspect of the invention is a method of treatment of the
human or non-human animal body for treating or preventing
fibrin-dependent microcirculation disorders or of disease states where
such microcirculation disorders are involved, said method comprising
insertion of a device according to claim 1 at a vascular site via
catheter placement at the site.

[0025]In a preferred embodiment, the structural member is composed of a
shape-memory alloy for radial expansion at a critical temperature by
activating a heat-recoverable memory diameter and the device is heated to
the critical temperature. In another preferred embodiment, the structural
member is composed of a heat-activated, shape memory polymer. In another
preferred embodiment, the structural member is composed of a metal and
designed for self-expansion.

[0026]In another preferred embodiment, the active ingredients can be
eluted simultaneously or in a specified sequence and with different
eluation characteristics.

[0027]Preferably dipyridamole or a pharmaceutically acceptable salt
thereof can be used alone in a monopreparation or in combination with
other antithrombotic agents for the reduction of vascular smooth muscle
cell proliferation induced by stents. Most preferred is the utilization
of dipyridamole in the presence of a dissolution mediation agent,
preferably an organic acid or a derivative thereof, in particular tataric
acid or cyclohexanedicarboxylic acid anhydride (CHD). Most preferred is a
composition comprising 1 part per weight dipyridamole and 0.1 to 50,
preferably 0.5 to 10, in particular 0.8 to 5 part per weight tataric acid
or cyclohexanedicarboxylic acid anhydride.

[0028]It is of advantage to maintain a tissue level which corresponds to a
plasma level of dipyridamole or mopidamol of about 0.2 to 5 μmol/L,
preferably of about 0.4 to 5 μmol/L, especially of about 0.5 to 2
μmol/L or particularly of about 0.8 to 1.5 μmol/L. This can be
achieved by direct loading of the polymer member of the stent or
dipyridamole controlled release, instant or the parenteral formulations
on the market, the controlled release formulations being preferred, for
instance those available under the trademark Persantin®, or, for the
combination therapy with low-dose aspirin, using those formulations
available under the trademark Asasantin® or Aggrenox®.
Dipyridamole controlled release formulations are also disclosed in
EP-A-0032562, instant formulations are disclosed in EP-A-0068191 and
combinations of aspirin with dipyridamole are disclosed in EP-A-0257344
which are incorporated by reference. In case of mopidamol also oral
controlled release, instant or a parenteral formulations can be used,
e.g. those disclosed in GB 1,051,218 or EP-A-0,108,898 which are
incorporated by reference, controlled release formulations being
preferred.

[0029]In another preferred embodiment, the depot of active ingredient(s)
of the stent according to the present invention may be reloaded with
dipyramidole and/or an additional active ingredient in vivo to maintain
bowel tissue level at a constant level with minimal variations.
Preferably such stents can be reloaded with active ingredient(s) wherein
the polymer member comprises hydrogels.

[0030]In addition to the implanted stent, dipyridamole or mopidamol may be
administered in a daily dosage of 50 to 900 mg, preferably 100 to 480 mg,
most preferred 150 to 400 mg. For long-term treatment it is of advantage
to administer repeat doses, such as a dose of 25 mg dipyridamole
controlled release or any other instant release formulation three or four
times a day. For parenteral administration dipyridamole could be given in
a dosage of 0.5 to 5 mg/kg body weight, preferably 1 to 3.5 mg/kg body
weight, during 24 hours.

[0031]Dipyridamole or mopidamol in combination with low-dose aspirin may
be administered orally in a daily dosage of 10 to 50 mg of aspirin
together with 100 to 600 mg of dipyridamole or mopidamol, preferably 160
to 480 mg of dipyridamole or mopidamol, for instance in a weight ratio
between 1 to 5 and 1 to 12, most preferred a weight ratio of 1 to 8, for
instance 50 mg of aspirin together with 400 mg of dipyridamole or
mopidamol.

[0032]Other antithrombotic compounds may be contained in the stent at 0.1
to 100 times, preferably at 0.3 to 30 times, most preferred at 0.3 to 10
times the clinically described dose (e.g. Rote Liste® 1999;
fradafiban, lefradafiban: EP-A-0483667), together with a daily dosage of
50 to 900 mg, preferably 100 to 480 mg, most preferred 150 to 400 mg of
dipyridamole or mopidamol.

[0033]For combination treatment using dipyridamole or mopidamol together
with ACE inhibitors any ACE inhibitor known in the art would be suitable,
e.g. benazepril, captopril, ceronapril, enalapril, fosinopril, imidapril,
lisinopril, moexipril, quinapril, ramipril, trandolapril or perindopril,
using dosages corresponding to those known in the art, for instance as
described in Rote Liste® 1999, Edition Cantor Verlag Aulendorf For
combination treatment using dipyridamole or mopidamol together with
Angiotensin TI receptor antagonists, any Angiotensin II receptor
antagonist known in the art would be suitable, e.g. the sartans such as
candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan,
olmesartan or tasosartan, using dosages corresponding to those known in
the art, for instance as described in Rote Liste® 1999, Edition
Cantor Verlag Aulendorf.

[0034]For combination treatment using dipyridamole or mopidamol together
with Ca-antagonists, any Ca-antagonist known in the art would be
suitable, e.g. nifedipine, nitrendipine, nisoldipine, nilvadipine,
isradipine, felodipine or lacidipine, using dosages corresponding to
those known in the art, for instance as described in Rote Liste®
1999, Editio Cantor Verlag Aulendorf.

[0035]For combination treatment using dipyridamole or mopidamol together
with statins, any statin known in the art would be suitable, e.g.
lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or
cerivastatin, using dosages corresponding to those known in the art, for
instance as described in Rote Liste® 1999, Editio Cantor Verlag
Aulendorf.

[0036]The additional drug embedded in the polymer member is, for example,
an anticoagulant, an antiproliferative agent, a vasodilator, a nitrate,
an antioxidant, antisense oligonucleotide, an antiplatlet agent, or a
clot dissolving enzyme. In a preferred embodiment, the drug is the
anticoagulant heparin.

[0037]In one embodiment, the polymer member is carried on the structural
member and is secured thereon by an adhesive. The adhesive can be, for
example, a biopolymer, such as a protein or a peptide. The adhesive can
also be prepared from a synthetic polymer which swells or is soluble in
water, and exemplary polymers are given below. In a preferred embodiment,
the adhesive is prepared from heparin.

[0038]These and other objects and features of the invention will be more
fully appreciated when the following detailed description of the
invention is read in conjunction with the accompanying drawings.

[0039]FIG. 1 illustrates cross-section of a strut of an endoprosthetic
device in accordance with one embodiment of the invention, where the
structural member (1) is encased by the polymer member (2) containing
dipyridamole, which may be coated by a second optional polymer member (3)
which allows to influence the release properties of the active
ingredients.

[0040]FIG. 2 illustrates an example of a 2-dimensional network of an
endoprosthetic device in accordance with one embodiment of the invention,
wherein zig-zag shaped struts (11) are cross-linked with additional
struts (12). The cell (4) formed from (11) and (12) allows to avoid that
side branches of the vessel are closed by the stent.

[0041]FIG. 3 illustrates an endoprosthetic device in accordance with one
embodiment of the invention, where the 2-dimensional network of struts
forms a cylinder shaped stent (100), the surface of which is partially
coated by additional rings (202), (203) comprising additional active
ingredients. Another ring (201) may be attached to the tube (100). The
rings themselves may consist of mashes allowing several of them to be
displayed on top of each other, without blocking side branches or
bifurcations of the vessel.

[0042]FIG. 4 illustrates a cross-section of a strut of an endoprosthetic
device in accordance with one embodiment of the invention, where the
structural member (1) is engraved with micro-deepenings or grooves along
the strut containing active drug such as dipyridamole or others.
Different micro deepenings (pockets) may contain different drugs as well
as different coatings to allow release with different pharmacokinetics.
(6), which may be coated by an optional polymer layer (5) which allows to
influence the release properties of the active ingredients.

[0043]The endoprosthetic device of the present invention, also referred to
herein as a stent, is designed for insertion at a vessel target site via
a catheter. As will be described, the low-profile, self-restraining stent
is designed for expansion in response to a stimulus and for
administration of a therapeutic compound for release at the target site.

[0044]In its most broad aspect, the device is composed of a structural
member having engraved micro-deepenings and/or an optional polymer
member. The two members are designed for coexpansion, where, in one
embodiment, the members are coextensive and, in another embodiment, the
polymer member encases the structural member. Each of these embodiments
will be described below in detail.

[0045]In a first embodiment of the device a structural member is encased
by the polymer member. The device is generally tubular or cylindrical in
shape. A structural member gives mechanical strength to the device and,
importantly, carries on its outer surfaces either and/or a polymer
member. In accordance with this first embodiment the polymer member
encases and/or surrounds the structural member.

[0046]In a particularly preferred embodiment the polymer member comprises
two or more layers of different polymers having different elution
properties on one structural member.

[0047]In a second embodiment of the device a structural member is engraved
with micro-deepenings. The device is generally tubular or cylindrical in
shape. A structural member gives mechanical strength to the device and,
importantly, carries on its outer surfaces said micro-deepenings.

[0048]The micro-deepenings are engraved on the structural member for
example by laser etching techniques, as will be described below. As will
be described below in more detail, the micro-deepenings are filled with a
pharmaceutical composition comprising e.g. dipyramidole and are covered
with a polymer coating, subsequently, the device is expanded by, for
example, exposing the structural member to a heat stimulus to activate a
material transition for recovery to a memory state or by a radial force,
such as provided by inflation of a balloon on a catheter.

[0049]The structural member of the device is formed preferably of a metal
or an alloy, including shape-memory alloys. Exemplary metals include
stainless steel, titanium, nickel, tantalum, cobalt, platinum and
iridium. Exemplary alloys include alloys of these metals, Cu--Zn--Al,
Cu--Al--Ni and shape-memory alloys of Ni--Ti alloys, known under the name
Nitinol, Bimetal or Memotal.

[0050]Most preferred are biodegradable structural member combined with
biodegradable polymer members having different biodegradation profiles.

[0051]The structural member of the device may also be formed from a
polymer, in particular a shape-memory polymer, and exemplary polymers are
given below.

[0052]The structural member can take a wide variety of geometries or
configurations, such as those described herein, and those known in the
art. Commercially available stents suitable for use as the structural
member include Johnson & Johnson's Interventional Stent System, a
low-profile stent from Arterial Vascular Engineering, the Cook Stent,
from Cook Cardiology Co., the BXT stent, from Cordis and the Cypher®,
Sirolimus (Sacrolimus) eluting stent from Cordis.

[0053]In a particular preferred embodiment micro-deepenings are engraved
into the upper and/or lower surface of the structural element. These
micro-deepenings contain a pharmaceutical composition, which comprises
dipyramidole and/or other active drugs.

[0054]The micro-deepenings can take a wide variety of geometries or
configurations, such as those described herein, and those known in the
art. Most preferred are micro-channels, which extend over the complete
surface of the strut or micro-wholes, which are plotted in certain
designs on the surface of the strut. These can be engraved into the
surface of the structural elements with the aid of laser etching
techniques. As a rule the micro-deepenings cover up to 40%, preferably 5
to 35%, in particular 10 to 20% of the upper and/or lower surface of the
structural element. Up to 80%, preferably 30 to 70%, in particular 40 to
60% of the height of the perimeter of the structural element can be
engraved in order to form micro-deepenings without destabilization of the
strut.

[0055]The polymer member may be of pave extension type or of shape-memory
type. Both types are suitable to provide a carrier basis for a variety of
organic and inorganic compounds. The carrier may be reloaded or
recharged, in the event that the plasma and/or tissue level drops below a
certain, desired level.

[0056]The polymer member of the device is formed from a shape-memory
polymer formulated to have a polymer-state transition that responds to a
selected stimulus. Upon exposure to the stimulus, the polymer transition
is activated and the polymer member moves from a contracted,
small-diameter state to an expanded, larger-diameter state.

[0057]Shape-memory polymers suitable for use in the present invention
include, for example, those described in U.S. Pat. No. 5,163,952, which
is incorporated by reference herein. In particular, the shape-memory
polymer is a methacrylate-containing or an acrylate-containing polymer,
and exemplary formulations are given below.

[0058]As discussed above, the shape-memory polymer member is characterized
in that it will attempt to assume a memory condition in response to a
stimulus which activates a polymer transition. Such a stimulus can be (i)
adsorption of heat by the polymer, (ii) adsorption of liquid by the
polymer, (iii) a change in pH in the liquid in contact with the polymer
or (iv) absorption of light.

[0059]Polymers responsive to heat are those that undergo a thermal
transition at a critical temperature. For example, such a thermal
transition can be a crystalline melting point of the either the main
chain or a side chain of the polymer, preferably between about
25°-100° C.; a glass-transition at a temperature of between
25°-100° C., more preferably between 25°-80°
C.; a liquid-crystal phase (mystifies) temperature transition; or a local
mode molecular transition.

[0060]Polymers responsive to adsorption of a liquid are formulated by
incorporating in the polymer a hydrophilic material, such a N-vinyl
pyrrolidone. Typically, upon exposure to an aqueous medium the N-vinyl
pyrrolidone absorbs water and swells, causing expansion of the polymer.

[0061]Polymers responsive to a change in pH are formulated by
incorporating pH sensitive materials into the polymer, such as
methacrylic acid or acrylic acid. Typically, these polymers swell in
response to a change in ionic environment, for movement between a small,
contracted state and a larger, expanded state.

[0062]In a preferred embodiment of the invention, the polymer member is
prepared from a polymer that is sensitive to heat. Typically, these
polymers are thermoplastic polymers which soften and take on a new shape
by the application of heat and/or pressure. These polymers can be
crosslinked to varying degrees so that the polymer will soften with heat
but not flow.

[0063]As discussed above, preferably, the shape-memory polymer for use in
forming the structural member of the device is a heat-sensitive, polymer,
and in particular a methacrylate-containing or an acrylate-containing
polymer.

[0064]An exemplary methacrylate-containing memory polymer is prepared by
mixing the monomers methyl methacrylate, polyethyleneglycol methacrylate,
butylmethacrylate in a 2:1.5:1 ratio. A crosslinker, such as
hexanedioldimethacrylate, and a thermal or UV initiator, such as benzoin
methyl ether or azobisisobutylnitrile (AIBN). The monomers can be
polymerized into a polymer for extrusion in a conventional extruder to
provide a length of a tubular structure or a flat sheet, which are
cross-linked by exposure to UV light, high energy electrons, gamma
radiation or heat. The monomers can also be polymerized in a transparent
spinning tube to form a tubular structure.

[0065]In experiments performed in support of the present invention,
described below, polymer members were formed from the monomers methyl
methacrylate, polyethyleneglycol methacrylate, and butylmethacrylate. The
monomers were crosslinked using hexanedioldimethacrylate and the
polymerization was initiated using Darocur. Another exemplary
thermoplastic polymer is polyethylene oxide, a heterochain thermoplastic
with a crystalline melting point around 65° C. Polyethylene oxide
can be crosslinked using a multifunctional acrylate or methacrylate, such
as triallylisocyanurate. Thermoplastic blends are also suitable memory
polymers, such as blends of polyethylene oxide with methylmethacrylate,
polyethylene, polycaprolactone, or trans-polyoctenamer (Vestenamer®).
Typically, between 10-90%, preferably 30-70%, of polyethylene oxide is
present in the blends. The blends can be crosslinked using conventional
multifunctional crosslinkers.

[0066]Other preferred polymers are those prepared by condensation
polymerization and free radical, or addition, polymerization.
Condensation polymers are those in which the molecular formula of the
repeat unit of the polymer chain lacks certain atoms present in the
monomer from which it was formed, or to which it can be degraded.
Exemplary condensation polymers include polyester, polyanhydride,
polyamide, polyurethane, cellulose, polysiloxane.

[0067]Radical chain, or addition polymers are those in which a loss of a
small molecule does not take place, as in condensation polymers. Polymers
formed by addition polymerization include polyethylene, polymethyl
methacrylate, polyvinyl chloride, and polyacrylonitrile.

[0068]The endoprosthetic device of the invention includes one or more
therapeutic agents, at least one of which being dipyridamole or
mopidamol, contained in the micro-deepenings and/or embedded in one or
more polymer members for release at the target site. The drugs may be
filled into the micro-deepenings by immersing the structural member into
a composition comprising the drug and optional evaporation of volatile
components. Thereupon the micro-deepenings may be covered by immersing
the structural member into a composition comprising a polymerizable
compound, optional evaporation of volatile components and heating or
irradiation.

[0069]Alternatively, the drugs are incorporated into the polymer member by
passive diffusion after fabrication of the member, or more preferably, by
addition of the drug to the polymer prior to extrusion of the polymer
member or prior to polymerization of the member.

[0071]The structural and polymer members of the device can take any number
of geometric configurations.

[0072]Preferably the structural member in the device is a self-expanding
stent, where the structural member in its contracted state is under
tension and in the absence of a restraining member, will expand to its
larger diameter state. The optional polymer member acts as a restraining
member for the structural member. The polymer member, formed of a
shape-memory polymer, is self-restraining, e.g., it maintains its
small-diameter condition until the polymer transition is activated. This
feature of the device is beneficial in maintaining a low device profile.

[0073]Expansion of the device may be achieved by exposing the polymer
member to a stimulus, such as heat, to activate the polymer transition.
As the polymer member expands, the structural member is no longer
restrained and coexpands with the polymer member.

[0074]It will be appreciated that the device can be formed of a variety of
materials and geometries. For example, the structural member can be
either a polymer or a metal and the flat sheet configuration may be
provided with slots, openings or gaps. It will further be appreciated
that the structural member and the polymer members can have different
geometries.

[0075]In preparing the endoprosthetic device of the present invention, the
optional polymer member and the structural members are each prepared and
then brought together to form the device. The selection of material for
each of the device members depends in part on the configuration of each
member and on whether the polymer member encases the structural member or
is coextensive with the structural member.

[0076]Preferably the polymer member is prepared from a monomer mixture
that is polymerized by exposure to UV light. The resulting polymer film
or tube has a thermal transition between about 35°-50° C.
and a polymer member is cut, using a precision blade or a laser, to the
desired geometry. The polymer member is placed in its small-diameter,
contracted state by heating the member above its thermal transition and
wrapping the member around an appropriate sized tube or rod. The member
is cooled to set the shape and removed from the tube. The member is then
slipped over a structural member, typically a metal or metal alloy stent
purchased from commercially available sources or prepared according to
known methods. For example, the Johnson & Johnson Interventional System
Stent, having a slotted tube design, can be used, as can a Cook Stent,
from Cook Cardiology. It will be appreciated that the polymer member can
be wrapped directly around the structural member rather than around a rod
or tube.

[0077]Alternatively, the polymer member is prepared from a polymer mixture
which is heated and blended in a conventional extruder to coat the struts
of the structural member or to form the desired geometry, either a
cylindrical tube or a rectangular strip. In the Example, the polymer
member is prepared from polyoctenylene and polyethylene glycol and
crosslinked with triallyl isocyanurate. Other polymers, such as
polyethylene, are also suitable.

[0078]After extrusion of a separate polymer member, the polymer member is
cut the appropriate length, converted into a mesh and/or slipped over the
structural member or co-wound with the structural member, depending on
the geometry of each member. For example, a structural member having a
flat rectangular shape can be prepared from Nitinol, available from Shape
Memory Applications (Santa Clara, Calif.).

[0079]The structural member and the polymer member, having the same
geometry are heated to above their respective transition temperatures and
co-wound around a stainless steel rod, having a diameter selected
according to the desired final stent size. The members are cooled while
being restrained in the contracted shape around the rod, to form the
device. In the case where the structural member and the polymer member of
the device are both formed of a polymer, the device may also include a
radio-opaque material, such as gold, stainless steel, platinum, tantalum,
bismuth, metal salts, such as barium sulfate, or iodine containing
agents, such as OmniPaque® (Sanofi Winthrop Pharmaceuticals). The
radio-opaque material may be incorporated into the polymer prior to
extrusion of device members, or a radio-opaque coating may be applied to
one or both of the members. The radio-opaque material provides a means
for identifying the location of the stent by x-rays or other imaging
techniques during or after stent placement. Preparation of a polymer
member having regions of radio-opacity, provided by gold particles
dispersed in the polymer member, is described in U.S. Pat. No. 5,674,242.

[0080]As discussed above, the endoprosthetic device of the present
invention is placed at a target vascular site by a transluminal
angioplasty catheter. The catheter is introduced over a conventional
guidewire and the stent is positioned within the target site using, for
example, fluoroscopic imaging.

[0081]Once the stent is properly positioned, a balloon is filled with a
liquid to stimulate the polymer-state transition of the polymer member.
As discussed above, the polymer transition may be thermally induced, may
be activated by a change in pH or adsorption of a liquid or may be light
induced by fiber optic. Upon exposure to the stimulus, the stent expands
from its small-diameter state toward its memory condition. For example, a
stent having a thermally-activated polymer transition is stimulated to
expand by filling the catheter balloon with a heated liquid, such as a
contrast agent heated to between about 40°-100° C. Heat
from the liquid is adsorbed by the polymer member. The catheter itself
may be specifically designed for injection of a heated liquid and for
better heat transfer. For example, the catheter may have a double lumen
for recirculation of the heated liquid in the balloon region of the
catheter.

[0082]The stimulus may also be a pH stimulus or a liquid stimulus, where a
buffer solution of a selected pH is introduced into the balloon. Small
openings in the balloon, introduced prior to placement of the stent
around the balloon, would allow the liquid to contact the stent.

[0083]In a preferred embodiment, the stimulus is a thermal stimulus, and a
heated liquid is introduced into the balloon. Heat from the liquid is
conducted convectively to the polymer stent, raising the temperature of
the stent to its thermal transition, such as a glass transition
temperature of between about 25°-100° C., more preferably
between 25°-80° C., and most preferably between
35°-70° C. The polymer member responds to the stimulus by
moving toward its memory condition. The structural member coexpands with
the polymer member, either in response to the thermal stimulus, the
radial force of the inflated balloon or by the self-expanding design of
the structural member. Expansion of the device continues until the
members are constrained by the vessel walls. Once the stent is fully
deployed with the segments in their expanded condition, the catheter may
be withdrawn over the guidewire, and the guidewire removed.

EXAMPLES

[0084]The following examples detail preparation of endoprosthetic devices
in accordance with the invention and are intended to be exemplary and in
no way limit the scope of the invention.

[0087]A stent has been prepared according to the method disclosed in U.S.
Pat. No. 5,674,242, the complete disclosure of which is hereby
incorporated by reference. The polymer member thereof has been made from
a mixture of 1 to 10 g dipyramidole, 1 to 50 g cyclohexanedicarboxylic
anhydride and 50 to 200 g of different methacrylate monomers.

[0088]The stent shows the following properties upon 16 hours of
incubation:

100% inhibition of DNA synthesis; strong release of dipyridamole.

Example 3

[0089]A stent has been prepared according to the method disclosed in U.S.
Pat. No. 5,674,242, the complete disclosure of which is hereby
incorporated by references. The polymer member thereof has been made from
a mixture of 1 to 10 g dipyramidole, 2 to 10 g tartaric acid and 50 to
200 g of different methacrylate monomers.

[0090]The stent shows the following properties upon 16 hours of
incubation:

96% inhibition of DNA synthesis; strong release of dipyridamole.

Example 4

[0091]A stent has been prepared according to the method disclosed in U.S.
Pat. No. 5,674,242, the complete disclosure of which is hereby
incorporated by references. The polymer member thereof has been made from
a mixture of 1 to 10 g dipyramidole and 50 to 200 g of different
methacrylate monomers.

[0092]The stent shows the following properties upon 16 hours of
incubation:

74% inhibition of DNA synthesis; weak release of dipyridamole.

[0093]Although the invention has been described with respect to particular
embodiments, it will be apparent to those skilled in the art that various
changes and modifications can be made without departing from the
invention.